SN3 SHORT NOTE 5M ★ High-yield

Describe the HLA system with its classes and functions. Add a note on its disease associations.

Pathology · 2nd Professional — Para-Clinical

Definition

The major histocompatibility complex (MHC), called the HLA system in man, is a cluster of genes on the short arm of chromosome 6 encoding cell-surface glycoproteins that present antigen to T lymphocytes.

The most polymorphic gene system known, which is why matching for transplantation is so difficult
Inherited as a haplotype — a set from each parent, so full siblings have a 1 in 4 chance of being HLA identical

Classes of Hla Molecule

Feature	Class I	Class II
Loci	HLA-A, B, C	HLA-DP, DQ, DR
Distribution	All nucleated cells and platelets	Antigen-presenting cells only — macrophages, dendritic cells, B cells
Presents to	CD8 cytotoxic T cells	CD4 helper T cells
Presents antigen from	Endogenous — viral and tumour proteins made inside the cell	Exogenous — phagocytosed material
Structure	One alpha chain + beta-2 microglobulin	Alpha and beta chains
Mnemonic	1 × 8 = 8	2 × 4 = 8

The "rule of eight" is the quickest way to remember it — class I with CD8, class II with CD4
Class III genes lie between them and encode complement C2, C4 and factor B, and TNF

Hla and Disease Associations

HLA	Disease	Strength
HLA-B27	Ankylosing spondylitis; reactive arthritis; psoriatic arthropathy; inflammatory bowel disease-associated arthritis	The strongest known — relative risk about 90
HLA-DR3 / DQ2	Coeliac disease; type 1 diabetes; SLE; Graves; myasthenia	Strong
HLA-DR4 / DQ8	Rheumatoid arthritis; type 1 diabetes	Strong
HLA-DR2	Multiple sclerosis; goodpasture syndrome; narcolepsy (DQB1*06:02)	Strong
HLA-B*57:01	Abacavir hypersensitivity	Testing is mandatory before prescribing
HLA-B*15:02	Carbamazepine-induced Stevens–Johnson syndrome in South-East Asians	Screening advised in at-risk populations
HLA-B*58:01	Allopurinol hypersensitivity	Notably relevant in Asian populations

CLINICAL PEARL

Association is not causation, and HLA typing is rarely diagnostic. About 8% of healthy people carry HLA-B27 and most never develop ankylosing spondylitis, so a positive result supports a clinical diagnosis but does not make one. The pharmacogenetic associations are different — testing before abacavir prevents a specific, severe and predictable reaction.

Functions of Hla

Antigen presentation to T cells — the central function; T cells recognise antigen only in association with self MHC (MHC restriction)
Positive and negative selection in the thymus, shaping the T cell repertoire and establishing central tolerance
Graft rejection — the principal barrier to transplantation
Susceptibility to disease, as above
Recognition of missing self by NK cells — loss of class I on a virus-infected or tumour cell triggers NK killing

Applied Aspects

HLA matching improves graft survival, and matters most for bone marrow, then kidney; less for liver and heart, where the practicalities dominate
A sibling has a 1 in 4 chance of being fully matched, which is why family typing is done first in transplantation
Bare lymphocyte syndrome — failure to express class II gives severe combined immunodeficiency, demonstrating how essential presentation is
Some viruses downregulate class I to evade cytotoxic T cells, but this exposes them to NK cells — a neat redundancy in the system
Paternity and forensic identification once relied on HLA typing, now largely replaced by DNA profiling

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